Due to a high degree of unpredictability, classic techniques of drug development are inventive. Mostly through a process of elimination, a large number of natural products and synthetic chemical compounds are screened for desired effects, using a series of increasingly complex systems, beginning with simple in vitro cell level assays, progressing to animals and finally human clinical trials. But, due to essential characteristics such as adsorption, distribution and metabolism, the initial in vitro tests that cannot take these features into account could eliminate a powerful drug that does not perform well in such simple systems. The drug could be metabolized to different compounds in animal models than in humans, which may also demonstrate different adsorption or distribution patterns. Or finally, compounds can look very promising all the way through clinical trials, but then demonstrate unpleasant side effects or a high degree of tolerance when used by the human population at large. It is never obvious which compound will continue to look promising as each stage of tests and development are initiated.
Control of tumorous growth has been achieved to a certain degree using oncolytic vinca alkaloids as antitumour agents alone or in combination with other antineoplastic drugs in cancer chemotherapy for more than 20 years. Approximately 30 alkaloids with a wide range of pharmacological activities have been extracted from the Vinca rosea(Catharanthus roseus), commonly known as the periwinkle plant. Of these, only vinleurosine, vinrosidine, vinblastine and vincristine possess significant anti-tumour activity. In particular, vinblastine andvincristine have been used widely as single agents and in combination with outer antineoplastic drugs in cancer chemotherapy. In addition to the naturally occurring alkaloids, some vinca alkaloid analogues have been synthesized by functional transformation or by semisynthetic processes (R. J. Cersosimo, et al., Pharmacotherapy 3:359-274, 1983; P. Mangency, et al., Org. Chem. 44:3765-3768, 1979; R. Maral, et al., Cancer Lett. 22:49-54, 1984).
Chemically, these vinca alkaloids have a dimeric asymmetric structure composed of 2 nuclei linked by a carbon-carbon bond; a dihydroindole nucleus (vindoline), which is the major alkaloid contained in the periwinkle, and the indole nucleus catharanthine (FIG. 1). The structural difference between vincristine and vinblastine exists at the R1 position while vinblastine and vindesine differ with regard to the R2 and R3 substituents.
The mode of action of the antineoplastic vinca alkaloids has yet to be completely understood. However, it has been established that the antitumour activity is directly related to the high binding affinity of these compounds fortubulin, the basic protein subunit of microtubules (R. A. Bender and B. Chabner, In: Chabner (ed) Pharmacol. Princ. of Cancer Treat., Saunders, Phil, Pa., p. 256,1982; W. A. Creasey, In: Hahn (ed) Antibiotica, Vol.2, Springer, Berlin, p.414,1979). The consensus is that these agents arrest cell mitosis at metaphase by preventing tubulin polymerization to form microtubules and by inducing depolymerization (R. J. Owellen and C. A. Hartke, Cancer Res., 36:1499-1504, 1976; R. H. Himes and R. N. Kersey, Cancer Res., 36:3798-3806, 1976; R. S. Camplejohn, Cell Tissue Kinet. 13:327-332, 1980). As such, the vinca alkaloids are cell cycle-specific anti-mitotic agents, or spindle poisons. The binding affinity of the vinca alkaloids to tubulin correlates poorly with the relative ability of vincristine, vinblastine and vindesine to inhibit cell growth (R.S. Camplejohn, supra; P. J. Ferguson and C. E. Cass, Cancer Res.,45:5480-5488, 1985). The major difference in anti-tumour activity between these drugs appears, therefore, to relate to the irretention in tumour tissue (P. Ferguson, supra; J. K. Hortonet al., Biochem. Pharnacol.37:3995-4000, 1988). In a similar vein, the different toxicity profiles of the vinca alkaloids seems related to tissue uptake and retention properties rather than to inherent tubulin binding affinity. For example, studies have demonstrated that vincristine is more potent than vinblastine or vindesine in blocking fast axoplasmic transport in nerve cells (S. Ochs and R. Worth, Proc. Am. Assoc. Cancer Res., 16:70, 1975; S. Y. Chan et al., J. Neurobiol. 1:251-264, 1980). In addition, it is taken up into nerves 4 times faster than the other drugs (Z. Iqbal and S. Ochs, J. Neurobiol., 11:251-264, 1980) and exhibits an extended terminal elimination phase of plasma clearance, suggesting a more prolonged exposure to vincristine than to the other vinca alkaloids (R. L. Nelson et al., Cancer Treat. Rev., 7:17-24, 1980).
The in vitro and in vivo differences observed between the vinca alkaloids are striking given the subtle chemical alterations displayed by the various agents relative to their large, complex molecular structure. For example, vincristine is very effective in treating human rhabdosarcomas transplanted in nude mice whereas vinblastine is not active in this system (N. Bruchovsky et al., Cancer Res. 25:1232-1238, 1965). This difference is obtained simply as a result of the substitution of an aldehyde group for a methyl group at the R1 position. Further, this chemical substitution leads to a shift in the toxicology profile such that peripheral neuropathy (in the absence of hematological toxicity) is dose limiting in humans for vincristine whereas anemia and leucopenia are typically dose limiting for vinblastine (W. P. Brads, Proc. Int. Vincaalkaloid Symposium, 95-123, 1980; S. S. Legha, Med. Toxicol., 1:421-427, 1986). A particularly interesting therapeutic profile has been observed for anew semisynthetic vinca alkaloid named Navelbine.TM. (vinorelbine,5'-noranhydroblastine). This compound is less potent than vinblastine and vincristine againstmurine P388 and L1210 leukemiabut is active against cells derived from human lung cancer whereas the other vinca alkaloids are inactive (S. Cros, et al., Seminars in Oncology, 16:15-20, 1989). As well, clinical trials on Navelbine.TM. support its utility in treating non-small cell lung cancer (A. Depierre et al., Am. J. Clin. Oncol., 14:155-119,1991; A. Yokoyama et al., Am. Soc. Clin. Oncol., 11:957,1992). The toxicity profile of this agent appears similar to that of vinblastine, where hematological toxicities and not neurological side effects are dose limiting. Vincristine has proved particularly useful as an intravenously administered oncolytic agent in combination with other oncolytic agents for the treatment of various cancers including central nervous-system leukemia, Hodgkin's disease, lymphosarcoma, reticulum-cell sarcoma, rhabdomyosarcoma, neuroblastoma, and Wilma tumor. It is for intravenous use only and the intratecal administration is uniformly fatal. Following single weekly doses, the most common adverse reaction is hair loss; the most troublesome are neuromuscular in origin. When single weekly doses of the drug are employed, the adverse reactions of leukopenia, neuritic pain, constipation, and difficulty in walking can occur. Other adverse reactions that have been reported are abdominal cramps, ataxia, foot drop, weightloss, optic atrophy with blindness, transient cortical blindness, fever, cranial nerve manifestations, parehesia and numbness of the digits, polyaria, dysuria, oral ulceration, headache, vomiting, diarrhea, and intestinal necrosis and/or perforation.
Navelbine.TM. (vinorelbine tartate) is a novel vinca alkaloid in which the catheranthine unit is the site of structural modification. Its anti-tumour activity is also thought to be due primarily to its ability to interfere with microtubule activity thereby inhibiting mitosis at metaphase through its interaction with tubulin. It is indicated in the treatment of advanced non-small cell lung cancer as a single agent or in combination, administered by intravenous route only. Its side effects include phlebitia or extravasion injury as it is a moderate vasicant. Studies on adverse reactions based on use of Navelbine.TM. as a single agent indicate Granculocytopenia as the major dose-limiting toxicity, although it was generally reversible and not cumulative overtime. Mild to moderate peripheral neutopathy manifested by pareathesia and hypesthesia are the most frequently reported neurologic toxicities, occurring in 10% of patients. Mild to moderate nausea occurs in roughly one-third of patients treated with Navelbine.TM. with a slightly lesser fraction experiencing constipation, vomiting, diarrhea, anorexia, and stomatitis.
Compounds exhibiting lessened toxic effects with equal or greater chernotherapeutic activity remain to be achieved. Thus, a need remains for a drug providing improved anti-tumour efficacy for the treatment of cancer.
It is, therefore, an object of the present invention to provide a method of treating cancer which comprises administering to a human patient suffering from cancer and in need of treatment, an amount of AHVB, effective to arrest or significantly slow the progress of the disease.
It is another object of the present invention to provide a method of using AHVB as an antitumour agent, comprising therapeutic amount of the chemical substance of the present invention to arrest tumorous growth.
The above and various other objects and advantages of the present invention are achieved by administration of a derivative of vinblastine, AHVB. Other objects and advantages will become evident from the following detailed description of the present invention.